3ZCL

X-ray Structure of c-Met kinase in complex with inhibitor (S)-3-(1-(1H-pyrrolo(2,3-b)pyridin-3-yl)ethyl)-N-isopropyl-(1,2,4)triazolo(4,3- b)pyridazin-6-amine

Summary for 3ZCL

• Entry DOI: 10.2210/pdb3zcl/pdb
• Descriptor: HEPATOCYTE GROWTH FACTOR RECEPTOR, (S)-3-(1-(1H-pyrrolo(2,3-b)pyridin-3-yl)ethyl)-N-isopropyl-(1,2,4)triazolo(4,3-b)pyridazin-6-amine (3 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 35200.79

Authors

McTigue, M.,Grodsky, N.,Ryan, K. (deposition date: 2012-11-20, release date: 2013-11-27, Last modification date: 2023-12-20)

Primary citation

Cui, J.J.,Shen, H.,Tran-Dube, M.,Nambu, M.,Mctigue, M.,Grodsky, N.,Ryan, K.,Yamazaki, S.,Aguirre, S.,Parker, M.,Li, Q.,Zou, H.,Christensen, J.
Lessons from (S)-6-(1-(6-(1-Methyl-1H-Pyrazol-4-Yl)-[1,2, 4]Triazolo[4,3-B]Pyridazin-3-Yl)Ethyl)Quinoline (Pf-04254644), an Inhibitor of Receptor Tyrosine Kinase C-met with High Protein Kinase Selectivity But Broad Phosphodiesterase Family Inhibition Leading to Myocardial Degeneration in Rats.
J.Med.Chem., 56:6651-, 2013

PubMed Abstract: The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.

PubMed: 23944843
DOI: 10.1021/JM400926X

Experimental method

X-RAY DIFFRACTION (1.4 Å)